Neonatal imprinting of tolerogenic properties in stromal cells from gut-draining lymph nodes by commensal microbiota

Foxp3+调节性T细胞(Tregs)在维持免疫稳态、自身耐受，尤其是粘膜耐受方面发挥着重要作用。绝大多数Foxp3+Tregs已经在胸腺中产生，然而，Foxp3+Tregs的一部分可以从外周的传统CD4+T细胞转化而来。这种Foxp3+Tregs的外周新生产生非常有效地发生在肠道引流淋巴结(LN)内，包括肠系膜淋巴结(MLN)。利用LN移植，我们最近不仅证明了LN基质细胞对肠道引流LN的高Treg诱导能力具有关键作用，而且这些引流LN的耐受特性稳定地印记在LN基质细胞中，并且不会受到皮肤局部微环境或炎性干扰(如胃肠道感染或慢性结肠炎)的显著影响。重要的是，在新生儿期与共生微生物群的接触可以被确定为负责在MLN基质细胞中稳定印记耐受属性的微环境因素，进一步强调了新生期对于发育完全功能的免疫系统的关键作用。在本项目中，我们旨在确定肠道微生物群在新生期MLN基质细胞中稳定印记耐受属性的分子机制。与优先方案的其他成员密切合作，我们将确定有助于这一过程的细菌物种和共生微生物区系衍生的分子介体，并将增加我们对共生微生物区系在MLN基质细胞表观遗传印记的分子途径的了解。我们将进一步研究在Foxp3+Tregs的外周从头生成过程中，共生微生物区系对Treg特异性表观遗传和转录特征形成的影响。最后，在优先方案其他成员的大力支持下，我们将调查新生儿感染和随后共生微生物群组成的变化对MLN基质细胞耐受性印记的长期后果。作为一个整体，通过确定有助于在MLN基质细胞中稳定印记耐受性的细菌物种、分子介体和表观遗传学机制，这一跨学科项目将进一步揭示Foxp3+Tregs与共生微生物区系之间复杂而密切的联系的一层。

Foxp3+ regulatory T cells (Tregs) play a central role for the maintenance of immune homeostasis, self-tolerance and particularly mucosal tolerance. The vast majority of Foxp3+ Tregs is generated already in the thymus, however, a subset of Foxp3+ Tregs can be converted from conventional CD4+ T cells in the periphery. This peripheral de novo generation of Foxp3+ Tregs very efficiently takes place within gut-draining lymph nodes (LNs), including mesenteric LNs (mLNs). Using LN transplantations, we could recently not only demonstrate that LN stromal cells critically contribute to the high Treg-inducing capacity of gut-draining LNs, but also that these tolerogenic properties of gut-draining LNs are stably imprinted within LN stromal cells and cannot be substantially influenced either by the local microenvironment of the skin or by inflammatory perturbations such as gastrointestinal infection or chronic colitis. Importantly, contact with commensal microbiota in the neonatal phase could be identified as the microenvironmental factor being responsible for the stable imprinting of tolerogenic properties in mLN stromal cells, further emphasizing the critical role of the neonatal period for the development of a fully functional immune system.In the present project, we aim to identify the molecular mechanisms by which intestinal microbiota stably imprint tolerogenic properties within mLN stromal cells in the neonatal period. In close cooperation with other members of the Priority Programme, we will identify bacterial species and commensal microbiota-derived molecular mediators that contribute to this process, and we will increase our knowledge of the molecular pathways being epigenetically imprinted in mLN stromal cells by commensal microbiota. We will furthermore study the impact of commensal microbiota on the formation of a Treg-specific epigenetic and transcriptional signature during peripheral de novo generation of Foxp3+ Tregs. Finally, with strong support from other members of the Priority Programme, we will investigate the long-lasting consequences of neonatal infections and subsequent changes in commensal microbiota composition on the imprinting of tolerogenic properties within mLN stromal cells. Viewed as a whole, by identifying bacterial species, molecular mediators and epigenetic mechanisms that contribute to the stable imprinting of tolerogenic properties in mLN stromal cells, this interdisciplinary project will shed further light into one of the layers of the complex and intimate connection of Foxp3+ Tregs with commensal microbiota.